Abstract Acetylcholine has been proposed to facilitate the formation of memory ensembles within the hippocampal CA3 network, by enhancing plasticity at CA3-CA3 recurrent synapses. Regenerative NMDA receptor (NMDAR) activation in CA3 neuron dendrites (NMDA spikes) increase synaptic Ca 2+ influx and can trigger this synaptic plasticity. Acetylcholine inhibits potassium channels which enhances dendritic excitability and therefore could facilitate NMDA spike generation. Here, we investigate NMDAR-mediated nonlinear synaptic integration in stratum radiatum (SR) and stratum lacunosum moleculare (SLM) dendrites in a reconstructed CA3 neuron computational model and study the effect of acetylcholine on this nonlinearity. We found that distal SLM dendrites, with a higher input resistance, had a lower threshold for NMDA spike generation compared to SR dendrites. Simulating acetylcholine by blocking potassium channels (M-type, A-type, Ca 2+ -activated, and inwardly-rectifying) increased dendritic excitability and reduced the number of synapses required to generate NMDA spikes, particularly in the SR dendrites. The magnitude of this effect was heterogeneous across different dendritic branches within the same neuron. These results predict that acetylcholine facilitates dendritic integration and NMDA spike generation in selected CA3 dendrites which could strengthen connections between specific CA3 neurons to form memory ensembles. Highlights - Using biophysical computational models of CA3 pyramidal neurons we estimated the quantitative effects of acetylcholine on nonlinear synaptic integration. - Nonlinear NMDA spikes can be triggered by fewer synapses in distal dendrites due to increased local input resistance. - Acetylcholine broadly reduces the number of synapses needed to trigger NMDA spikes, but the magnitude of the effect varies across dendrite branches within a single neuron. - No single potassium channel type is the dominant mediator of the excitability effects of acetylcholine.

Acetylcholine boosts dendritic NMDA spikes in a CA3 pyramidal neuron model